Methods and systems for renal neuromodulation

ABSTRACT

Methods for treating preventing or decreasing the likelihood of a human patient developing hypertension and associated systems and methods are disclosed herein. One aspect of the present technology, for example, is directed to methods for therapeutic renal neuromodulation that partially inhibit sympathetic neural activity in renal nerves proximate a renal blood vessel of a human patient. This reduction in sympathetic neural activity is expected to therapeutically treat one or more conditions associated with hypertension or prehypertension of the patient. Renal sympathetic nerve activity can be modulated, for example, using an intravascularly positioned catheter carrying a neuromodulation assembly, e.g., a neuromodulation assembly configured to use mechanically-induced, electro-magnetically-induced, and/or chemically-induced approaches to modulate the renal nerves.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the following applications:

U.S. Provisional Patent Application No. 61/972,174, filed Mar. 28, 2014;

U.S. Provisional Patent Application No. 61/967,891, filed Mar. 28, 2014;

U.S. Provisional Patent Application No. 61/967,873, filed Mar. 28, 2014;

U.S. Provisional Patent Application No. 61/967,874, filed Mar. 28, 2014;

U.S. Provisional Patent Application No. 61/967,876, filed Mar. 28, 2014;

U.S. Provisional Patent Application No. 61/967,880, filed Mar. 28, 2014;

U.S. Provisional Patent Application No. 62/018,919, filed Jun. 30, 2014;

U.S. Provisional Patent Application No. 62/050,083, filed Sep. 13, 2014;

U.S. Provisional Patent Application No. 62/056,658, filed Sep. 29, 2014;

U.S. Provisional Patent Application No. 62/060,627, filed Oct. 7, 2014;and

U.S. Provisional Patent Application No. 62/101,936, filed Jan. 9, 2015.

All of the foregoing applications are incorporated herein by referencein their entireties. Further, components and features of embodimentsdisclosed in the applications incorporated by reference may be combinedwith various components and features disclosed and claimed in thepresent application.

TECHNICAL FIELD

The present technology relates generally to methods and systems forcatheter-based renal neuromodulation. In particular, several embodimentsare directed to treatment of hypertension and/or improving one or moremeasurable physiological parameters corresponding to hypertension usingrenal neuromodulation and associated systems and methods.

BACKGROUND

The sympathetic nervous system (SNS) is a primarily involuntary bodilycontrol system typically associated with stress responses. Fibers of theSNS extend through tissue in almost every organ system of the humanbody. For example, some fibers extend from the brain, intertwine alongthe aorta, and branch out to various organs. As groups of fibersapproach specific organs, fibers particular to the organs can separatefrom the groups. Signals sent via these and other fibers can affectcharacteristics such as pupil diameter, gut motility, and urinaryoutput. Such regulation can have adaptive utility in maintaininghomeostasis or in preparing the body for rapid response to environmentalfactors. Chronic activation of the SNS, however, is a common maladaptiveresponse that can drive the progression of many disease states.Excessive activation of the renal SNS in particular has been identifiedexperimentally and in humans as a likely contributor to the complexpathophysiology of hypertension, states of volume overload (such asheart failure), and progressive renal disease. As examples, radiotracerdilution has demonstrated increased renal norepinephrine (NE) spilloverrates in patients with essential hypertension.

Sympathetic nerves of the kidneys terminate in the blood vessels, thejuxtaglomerular apparatus, and the renal tubules. Stimulation of therenal sympathetic nerves can cause increased renin release, increasedsodium (Na⁺) reabsorption, and a reduction of renal blood flow. Theseneural regulation components of renal function are considerablystimulated in disease states characterized by heightened sympathetictone as well as likely contribute to increased blood pressure inhypertensive patients. The reduction of renal blood flow and glomerularfiltration rate as a result of renal sympathetic efferent stimulation islikely a cornerstone of the loss of renal function in cardio-renalsyndrome (i.e., renal dysfunction as a progressive complication ofchronic heart failure). Pharmacologic strategies to thwart theconsequences of renal efferent sympathetic stimulation include centrallyacting sympatholytic drugs, beta blockers (intended to reduce reninrelease), angiotensin converting enzyme inhibitors and receptor blockers(intended to block the action of angiotensin II calcium channelblockers), vasodilators (to counteract peripheral vasoconstrictioncaused by increased sympathetic drive), aldosterone blockers (to blockthe actions of increased aldosterone released from activation of theRAAS and aldosterone activation consequent to renin release), anddiuretics (intended to counter the renal sympathetic mediated sodium andwater retention). These pharmacologic strategies, however, havesignificant limitations including limited efficacy, compliance issues,side effects, and others.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present disclosure can be better understood withreference to the following drawing(s). The components in the drawingsare not necessarily to scale. Instead, emphasis is placed onillustrating clearly the principles of the present disclosure.

FIG. 1 illustrates an intravascular neuromodulation system configured inaccordance with an embodiment of the present technology.

FIG. 2 illustrates modulating renal nerves with a neuromodulation systemconfigured in accordance with an embodiment of the present technology.

FIGS. 3A-3B illustrate a pattern of treatment locations that can beformed on the interior vessel wall in accordance with an embodiment ofthe present technology.

DETAILED DESCRIPTION

The present technology is directed to apparatuses, systems, and methodsfor treating hypertension and/or improving one or more measurablephysiological parameters corresponding to hypertension using renalneuromodulation. For example, some embodiments include performingtherapeutically-effective renal neuromodulation on a patient diagnosedwith hypertension. As discussed in greater detail below, renalneuromodulation can include rendering neural fibers inert, inactive, orotherwise completely or partially reduced in function. This result canbe mechanically-induced, electro-magnetically-induced, or induced byanother mechanism during a renal neuromodulation procedure, e.g., aprocedure including percutaneous transluminal intravascular access.

Specific details of several embodiments of the technology are describedbelow with reference to FIGS. 1-3B. Although many of the embodiments aredescribed herein with respect to mechanically-induced and/orelectro-magnetically-induced approaches, other treatment modalities inaddition to those described herein are within the scope of the presenttechnology. Additionally, several other embodiments of the technologycan have different configurations, components, or procedures than thosedescribed herein. A person of ordinary skill in the art, therefore, willaccordingly understand that the technology can have other embodimentswith additional elements and that the technology can have otherembodiments without several of the features shown and described belowwith reference to FIGS. 1-3B.

As used herein, the terms “distal” and “proximal” define a position ordirection with respect to the treating clinician or clinician's controldevice (e.g., a handle assembly). “Distal” or “distally” can refer to aposition distant from or in a direction away from the clinician orclinician's control device. “Proximal” and “proximally” can refer to aposition near or in a direction toward the clinician or clinician'scontrol device.

I. Renal Neuromodulation

Renal neuromodulation is the partial or complete incapacitation or othereffective disruption of nerves innervating the kidneys. In particular,renal neuromodulation can include inhibiting, reducing, and/or blockingneural communication along neural fibers (i.e., efferent and/or afferentnerve fibers) innervating the kidneys. Such incapacitation can belong-term (e.g., permanent or for periods of months, years, or decades)or short-term (e.g., for periods of minutes, hours, days, or weeks).While long-term disruption of the renal nerves can be desirable foralleviating symptoms and other sequelae associated with hypertensionover longer periods of time, short-term modulation of the renal nervesmay also be desirable. For example, some patients may benefit fromshort-term modulation to address acute symptoms of hypertension.

Intravascular devices that reduce sympathetic nerve activity byapplying, for example, mechanical force, pressure and/or mechanicalstimulation or disruption to a target site in the renal artery haverecently been shown to reduce blood pressure in patients with resistanthypertension. For purposes of this disclosure, a person has “resistanthypertension” when that person's systolic blood pressure remains at orabove 140 mm Hg despite adherence to at least three maximally tolerateddoses of antihypertensive medications from complementary classes,including a diuretic at an appropriate dose.

The renal sympathetic nerves arise from T10-L2 and follow the renalartery to the kidney. The sympathetic nerves innervating the kidneysterminate in the blood vessels, the juxtaglomerular apparatus, and therenal tubules. Stimulation of renal efferent nerves results in increasedrenin release (and subsequent RAAS activation) and sodium retention anddecreased renal blood flow. These neural regulation components of renalfunction are considerably stimulated in disease states characterized byheightened sympathetic tone and likely contribute to increased bloodpressure in hypertensive patients. The reduction of renal blood flow andglomerular filtration rate as a result of renal sympathetic efferentstimulation is likely a cornerstone of the loss of renal function incardio-renal syndrome (i.e., renal dysfunction as a progressivecomplication of chronic heart failure).

Various techniques can be used to partially or completely incapacitateneural pathways, such as those innervating the kidney. The applicationof mechanical force and/or electro-magnetic energy to tissue can induceone or more desired effects on localized regions along all or a portionof the renal artery and adjacent regions of the renal plexus RP, whichlay intimately within or adjacent to the adventitia of the renal artery.Some embodiments of the present technology, for example, includecatheter or stent devices for applying mechanical force, which can beused for therapeutically-effective renal neuromodulation. For example,particular devices can be configured to deliver mechanical force,pressure, stimulation and/or disruption at a treatment site. Suitabledevices can include, for example, catheters having probes, baskets,balloons, fluid dispersion mechanisms, and/or vibration components,stents, or other suitable mechanical disrupting modalities alone or incombination.

Mechanical disruptive effects can be achieved by both temporary as wellas permanently implanted structures or devices that impart force orpressure on the interior wall of the renal artery to partially orcompletely disrupt the ability of a nerve to transmit a signal. In caseswhere vascular structures are affected, the target neural fibers may bedenied perfusion resulting in necrosis of the neural tissue.

In some embodiments, fluid dispersion can impart force against oradjacent to the interior wall of the renal artery that may at leastpartially modulate neural function. The fluid, in one example, couldinclude one or more anesthetic agents and contrast agents. A variety ofsuitable techniques can be used to deliver fluids to tissue at atreatment location. For example, fluids can be delivered via one or moredevices, such as needles originating outside the body or within thevasculature or delivery pumps (see, e.g., U.S. Pat. No. 6,978,174, thedisclosure of which is hereby incorporated by reference in itsentirety). In an intravascular example, a catheter can be used tointravascularly position a therapeutic element including a plurality ofneedles (e.g., micro-needles) that can be retracted or otherwise blockedprior to deployment.

In some embodiments, a treatment procedure can include applying asuitable mechanical energy or mechanically-disruptive element at atreatment location in a testing step followed by a treatment step. Thetesting step, for example, can include applying a first force at a lowerintensity and/or for a shorter duration than during the treatment step.This can allow an operator to determine (e.g., by neural activitysensors and/or patient feedback) whether nerves proximate the treatmentlocation are suitable for modulation. Performing a testing step can beparticularly useful for treatment procedures in which targeted nervesare closely associated with nerves that could cause undesirable sideeffects if modulated during a subsequent treatment step.

II. Selected Examples of Neuromodulation Modalities

Complete or partial renal neuromodulation in accordance with embodimentsof the present technology can be mechanically-induced,electro-magnetically-induced, or induced in another suitable manner orcombination of manners at one or more suitable locations during atreatment procedure. For example, neuromodulation may be achieved usingvarious devices, such as stents, catheters having probes, baskets,balloons, fluid dispersion mechanisms, vibration components, or othersuitable mechanical disrupting modalities alone or in combination. Insome embodiments, renal neuromodulation induced by mechanical means canbe combined with other therapies such delivery of electrical energy(e.g., radiofrequency (RF) energy), cryotherapy, and/or drug therapy fortreating hypertension.

In those embodiments of the methods disclosed herein that utilizepartial neuromodulation, the level of mechanical force delivered to therenal artery and surrounding tissue may be different than the level thatis normally delivered for complete neuromodulation. For example, partialneuromodulation using mechanical force may use alternate devices,algorithms or different power levels for complete neuromodulation.Alternatively, partial neuromodulation methods may utilize the samelevel of mechanical force, but delivered to a different treatment siteand/or pattern of treatment locations within the blood vessel. Incertain embodiments, partial neuromodulation may be achieved using adevice that differs from a device used for complete neuromodulation. Incertain embodiments, a particular treatment or mechanically-disruptingmodality may be more suitable for partial neuromodulation than othertreatment or energy modalities.

In some embodiments, complete or partial renal neuromodulation caninclude a mechanical disruptive treatment modality alone or incombination with another treatment modality. Mechanical-based treatmentcan include delivering mechanical force or pressure and/or another formof mechanical stimulation to tissue at a treatment location to stimulateand/or affect the tissue in a manner that modulates neural function. Forexample, sufficiently stimulating at least a portion of a sympatheticrenal nerve can slow or potentially block conduction of neural signalsto produce a prolonged or permanent reduction in renal sympatheticactivity. A variety of suitable types of devices can be used tostimulate and/or mechanically disrupt tissue at a treatment location.For example, as mentioned above, devices suitable for mechanicallydisrupting tissue can include stents, catheters having probes, baskets,balloons, fluid dispersion mechanisms, vibration components, or othersuitable mechanical disrupting modalities alone or in combination.Furthermore, the mechanical disruption and/or pressure can be appliedfrom within the body (e.g., within the vasculature or other body lumensin a catheter-based approach) and/or from outside the body, e.g., via anapplicator positioned outside the body. In some embodiments, mechanicalforce or pressure applied can be used to reduce damage to non-targetedtissue when targeted tissue adjacent to the non-targeted tissue issubjected to mechanical disruption.

The use of vibratory mechanical energy can be beneficial in certainembodiments. In some embodiments, for example, the vibration device maybe a catheter device with a vibration element or an array of vibratingelements on its distal tip.

In some embodiments, renal neuromodulation can include a fluid-basedtreatment modality alone or in combination with another treatmentmodality. In an intravascular example, a catheter can be used tointravascularly position a therapeutic element including one or morefluid-dispersing devices. For example, the therapeutic element caninclude a plurality of needles (e.g., micro-needles) that can beretracted or otherwise blocked prior to deployment.

Renal neuromodulation in conjunction with the methods and devicesdisclosed herein may be carried out at a location proximate (e.g., at ornear) a vessel or chamber wall (e.g., a wall of a renal artery, one ormore branch vessels from the renal artery, a ureter, a renal pelvis, amajor renal calyx, a minor renal calyx, and/or another suitablestructure), and the treated tissue can include tissue proximate thetreatment location. For example, with regard to a renal artery, atreatment procedure can include modulating nerves in the renal plexus,which lay intimately within or adjacent to the adventitia of the renalartery.

In certain embodiments, the efficacy of partial neuromodulation may bemonitored by measuring the levels of one or more biomarkers associatedwith neuromodulation including, for example, proteins or non-proteinmolecules that exhibit an increase or decrease in level or activity inresponse to neuromodulation.

III. Methods for Treatment of Hypertension

Disclosed herein are several embodiments of methods directed totreatment of hypertension and other conditions (e.g., conditions relatedto hypertension) using catheter-based renal neuromodulation. The methodsdisclosed herein are expected to represent various advantages over anumber of conventional approaches and techniques in that they may allowfor potential targeting of the cause(s) of hypertension and/or improvingone or more measurable physiological parameters corresponding tohypertension, thereby providing for localized treatment and limitedduration treatment regimens (e.g., one-time treatment), thereby reducingpatient long-term treatment compliance issues.

In certain embodiments, the methods provided herein comprise performingrenal neuromodulation, thereby decreasing blood pressure and/orsympathetic renal nerve activity. In certain embodiments, renalneuromodulation may be repeated one or more times at various intervalsuntil a desired blood pressure and/or sympathetic nerve activity levelor another therapeutic benchmark is reached. In one embodiment, adecrease in blood pressure and/or sympathetic nerve activity may beobserved via a marker of blood pressure and/or sympathetic nerveactivity in patients having hypertension, such as decreased levels ofplasma norepinephrine (noradrenaline). Other measures or markers ofblood pressure and/or sympathetic nerve activity can include musclesympathetic nerve activity (MSNA), NE spillover, and/or heart ratevariability. In another embodiment, other measurable physiologicalparameters or markers, such as improved blood pressure control, changesin aldosterone-to-renin ratio, changes in a salt suppression test,changes in blood plasma levels of potassium, etc., can be used to assessefficacy of the renal neuromodulation treatment for patients havinghypertension.

In certain embodiments of the methods provided herein, renalneuromodulation is expected to result in a change in blood pressureand/or sympathetic nerve activity over a specific timeframe. Forexample, in certain of these embodiments, blood pressure and/orsympathetic nerve activity levels are decreased over an extendedtimeframe, e.g., within 1 month, 2 months, 3 months, 6 months, 9 monthsor 12 months post-neuromodulation.

In several embodiments, the methods disclosed herein may comprise anadditional step of measuring blood pressure and/or sympathetic nerveactivity levels, and in certain of these embodiments, the methods canfurther comprise comparing the activity level to a baseline activitylevel. Such comparisons can be used to monitor therapeutic efficacy andto determine when and if to repeat the neuromodulation procedure (e.g.,immediately, after a predetermined period of time, repeated proceduresat set periods of time, etc.). In certain embodiments, a baseline bloodpressure and/or sympathetic nerve activity level is derived from thesubject undergoing treatment. For example, baseline blood pressure(e.g., at or above 140 mm Hg, at or above 160 mm Hg) and/or sympatheticnerve activity level may be measured in the subject at one or moretimepoints prior to treatment. A baseline blood pressure and/orsympathetic nerve activity value may represent blood pressure and/orsympathetic nerve activity at a specific timepoint before renalneuromodulation, or it may represent an average activity level at two ormore timepoints prior to renal neuromodulation. In certain embodiments,the baseline value is based on blood pressure and/or sympathetic nerveactivity immediately prior to treatment (e.g., after the subject hasalready been catheterized). Alternatively, a baseline value may bederived from a standard value for blood pressure and/or sympatheticnerve activity observed across the population as a whole or across aparticular subpopulation. In certain embodiments, post-neuromodulationsympathetic nerve activity levels are measured in extended timeframespost-neuromodulation, e.g., 3 months, 6 months, 12 months, etc.post-neuromodulation.

In certain embodiments of the methods provided herein, the methods aredesigned to decrease blood pressure and/or sympathetic nerve activity toa target level. In these embodiments, the methods include a step ofmeasuring blood pressure and/or sympathetic nerve activity levelspost-neuromodulation (e.g., 3 months post-treatment, 6 monthspost-treatment, 12 months post-treatment, etc.) and comparing theresultant activity level to a baseline activity level as discussedabove. In certain of these embodiments, the treatment is repeated untilthe target sympathetic nerve activity level is reached. In otherembodiments, the methods are simply designed to decrease blood pressureand/or sympathetic nerve activity below a baseline level withoutrequiring a particular target activity level.

Renal neuromodulation may be performed on a patient diagnosed withhypertension to reduce one or more measurable physiological parameterscorresponding to the hypertension. In some embodiments, renalneuromodulation may decrease blood pressure, decreasealdosterone-to-renin ratio, change the result of a salt suppression test(e.g., negative result), increase blood plasma levels of potassium, etc.For example, renal neuromodulation may reduce the severity and/orfrequency of hypertension in a patient. A reduction in blood pressurecan be, for example, by at least about 5%, 10%, or a greater amount asdetermined by average blood pressure analysis before and after (e.g., 1,3, 6, or 12 months after) a renal neuromodulation procedure. In certainembodiments, a human patient treated with renal neuromodulation viamechanical energy and/or electro-magnetic energy can have a decrease inoffice systolic blood pressure of at least about 10 mm Hg, at leastabout 12 mm Hg, at least about 13 mm Hg, at least about 14 mm Hg, atleast about 21 mm Hg, or at least about 33 mm Hg from the patient'sbaseline systolic blood pressure. In other embodiments, a human patienttreated with renal neuromodulation via mechanical energy and/orelectro-magnetic energy can have a decrease in a 24-hour ambulatoryblood pressure of at least about 5 mm Hg, at least about 6 mm Hg, or atleast about 11 mm Hg from the patient's baseline 24-hour ambulatorysystolic blood pressure.

Corresponding results may be obtained with plasma aldosteroneconcentration, plasma renin activity, aldosterone-to-renin ratio, and/orblood plasma levels of potassium (e.g., to assess reversal of ahypokalemia state). A reduction in plasma aldosterone concentration canbe, for example, by at least about 5%, 10% or a greater amount asdetermined by blood analysis. In a specific example, plasma aldosteroneconcentration can be reduced by an amount up to about 90% as determinedby blood analysis. In another instance, a reduction in analdosterone-to-renin ratio can be, for example, by at least about 5%,10% or a greater amount (e.g., about 50%, about 80%, about 90%) asdetermined by blood analysis and calculation. In the case of secondaryhypertension, renal neuromodulation may provide a reduction in plasmarenin activity, for example, by about 5%, 10% or a greater amount asdetermined by blood analysis. In a specific example, plasma reninactivity can, for example, be reduced by an amount up to about 80% asdetermined by blood analysis. Additionally, an increase in blood plasmalevels of potassium can be, for example, by about 5%, 10% or a greateramount as determined by blood analysis. For example, normal plasmapotassium levels are approximately between 3.5 to about 5.0 mEq/L.Accordingly, hypokalemia can be characterized by a plasma potassiumlevel less than about 3.5 mEq/L.

In addition to or instead of affecting the blood pressure or hypokalemiain a patient, renal neuromodulation may efficaciously treat othermeasurable physiological parameter(s) or sequelae corresponding tohypertension. For example, in some embodiments, renal neuromodulationmay reduce the severity and/or frequency of headaches, musclecramps/spasms, muscle fatigue, numbness, tingling, metabolic alkalosis,polyuria, polydipsia, and/or patient reported fatigue. Furthermore,renal neuromodulation may improve markers of renal injury (e.g., serumBUN levels, serum creatinine levels, serum cystatin C levels,proteinuria levels, NGAL levels, and Kim-1 levels) or may improve renalfunction (e.g., slow a decline in glomerular filtration rate) in apatient, prevent end-stage renal disease, etc. These and other resultsmay occur at various times, e.g., directly following renalneuromodulation or within about 1 month, 3 months, 6 months, a year, ora longer period following renal neuromodulation.

As previously discussed, the progression of hypertension may be relatedto sympathetic overactivity and, correspondingly, the degree ofsympathoexcitation in a patient may be related to the severity of theclinical presentation of the hypertension. The kidneys are strategicallypositioned to be both a cause (via afferent nerve fibers) and a target(via efferent sympathetic nerves) of elevated central sympathetic drive.In some embodiments, renal neuromodulation is used to reduce centralsympathetic drive in a patient diagnosed with hypertension in a mannerthat treats the patient for the hypertension and/or sequelae associatedwith hypertension. In some embodiments, for example, MSNA can be reducedby at least about 10% in the patient within about three months after atleast partially inhibiting sympathetic neural activity in nervesproximate a renal artery of the kidney. Similarly, in some instanceswhole body NE spillover can be reduced at least about 20% in the patientwithin about three months after at least partially inhibitingsympathetic neural activity in nerves proximate a renal artery of thekidney. Additionally, measured NE content (e.g., assessed via renalbiopsy, assessed in real-time via intravascular blood collectiontechniques, etc.) can be reduced (e.g., at least about 5%, 10%, or by atleast 20%) in the patient within about three months after at leastpartially inhibiting sympathetic neural activity in nerves proximate arenal artery innervating the kidney.

In one prophetic example, a patient diagnosed with hypertension can besubjected to a baseline assessment indicating a first set of measurableparameters corresponding to the hypertension. Such parameters caninclude, for example, blood pressure, sodium level, potassium level,plasma aldosterone concentration, plasma renin activity,aldosterone-to-renin ratio, salt suppression, levels of components ofthe RAAS (e.g., angiotensinogen II levels), urinary Na⁺/K⁺ levels,levels of central sympathetic drive (e.g., MSNA, whole body NEspillover), and markers of renal damage or measures of renal function(e.g. creatinine level, estimated glomerular filtration rate, blood ureanitrogen level, creatinine clearance, cystatin-C level, NGAL levels,KIM-1 levels, presence of proteinuria or microalbuminuria, urinaryalbumin creatinine ratio). Following baseline assessment, the patientcan be subjected to a renal neuromodulation procedure. Such a procedurecan, for example, include any of the treatment modalities describedherein or another treatment modality in accordance with the presenttechnology. The treatment can be performed on nerves proximate one orboth kidneys of the patient. Following the treatment (e.g., 1, 3, 6, or12 months following the treatment), the patient can be subjected to afollow-up assessment. The follow-up assessment can indicate a measurableimprovement in one or more physiological parameters corresponding to thehypertension.

The methods described herein address the sympathetic excess that isthought to be an underlying cause of hypertension or a central mechanismthrough which hypertension manifests its multiple deleterious effects onpatients. In contrast, known therapies currently prescribed for patientshaving hypertension typically address only specific manifestations ofhypertension. Additionally, these known therapies can have significantlimitations including limited efficacy, undesirable side effects and canbe subject to adverse or undesirable drug interactions when used incombination. Moreover, conventional therapies may require the patient toremain compliant with the treatment regimen over time. In contrast,renal neuromodulation can be a one-time or otherwise limited treatmentthat would be expected to have durable benefits to inhibit the long-termdisease progression and thereby achieve a favorable patient outcome.

In some embodiments, patients diagnosed with hypertension can be treatedwith renal neuromodulation alone. However, in other embodiments,patients diagnosed with hypertension can be treated with one or morecombinations of therapies for treating primary causative modes ofhypertension and/or sequelae of hypertension. For example, combinationsof therapies can be tailored based on specific manifestations of thedisease in a particular patient. In a specific example, patients havinghypertension and presenting hypertension can be treated with bothantihypertensive drugs and renal neuromodulation. In another example,renal neuromodulation can be combined with angiotensin-converting-enzyme(ACE) inhibitors (e.g., Captopril, Zofenopril, Enalapril, Ramipril,Fosinopril, etc.) or angiotensin receptor blockers (ARBs) (e.g.,Valsartan, Telmisartan, Losartan, etc.) to treat secondary hypertension.Primary hypertension can be treated using a combination of renalneuromodulation and surgical removal of a focal aldosterone producingadenoma (e.g., adrenalectomy) or drugs that block the secretion ofaldosterone (e.g., spironolactone, eplerenone). In patients alsoexperiencing hypokalemia, intravenous (IV) supplementation, oralpotassium chloride supplements, and/or dietary modifications canaccompany renal neuromodulation.

In further embodiments, patients taking maximum tolerated doses of oneor more antihypertensive drugs with a combination/cocktail of selecteddrugs may also be treated with renal neuromodulation. In someembodiments, this combined therapy may result in the patient being ableto reduce the number of drugs being taken in the combination/cocktail,lower the dosage of one or more of the drugs, and/or eliminate one ormore of the drugs. In still another embodiment, the combined therapy mayresult in other modifications to the patient's drug regimen (e.g.,adjustments/exchanges/alterations of the combination/cocktail ofselected drugs, change classes of antihypertensive drugs, etc.) to helpfurther improve/enhance treatment of the patient's hypertension andrelated conditions.

Treatment of hypertension or related conditions may refer to preventingthe condition, slowing the onset or rate of development of thecondition, reducing the risk of developing the condition, preventing ordelaying the development of symptoms associated with the condition,reducing or ending symptoms associated with the condition, generating acomplete or partial regression of the condition, or some combinationthereof.

IV. Selected Embodiments of Renal Neuromodulation Systems and Devices

FIG. 1 illustrates a renal neuromodulation system 10 configured inaccordance with an embodiment of the present technology. The system 10,for example, may be used to perform therapeutically-effective renalneuromodulation on a patient diagnosed with hypertension (e.g., a humanpatient having a systolic blood pressure at or above 140 mm Hg or at orabove 160 mm Hg). The system 10 includes an intravascular treatmentdevice 12 operably coupled to an energy source or console 26 (e.g.,power source, inflation source, etc.). In the embodiment shown in FIG.1, the treatment device 12 (e.g., a catheter) includes an elongatedshaft 16 having a proximal portion 18, a handle 34 at a proximal regionof the proximal portion 18, and a distal portion 20 extending distallyrelative to the proximal portion 18. The treatment device 12 furtherincludes a neuromodulation assembly or treatment section 21 at thedistal portion 20 of the shaft 16. The neuromodulation assembly 21 caninclude a mechanical device configured to be delivered to a renal bloodvessel (e.g., a renal artery) in a low-profile configuration.

In one embodiment, for example, the neuromodulation assembly 21 caninclude a probe having a distal portion configured to bend such that theprobe presses against the wall of the renal artery. In anotherembodiment, the neuromodulation assembly 21 can include a basket havinga plurality of expandable legs. In some arrangements, the basket can beconfigured to move from a low profile configuration for delivery throughthe vasculature to a deployed configuration in which the legs pressagainst the wall of the renal artery. In other embodiments, theneuromodulation assembly 21 may comprise a balloon configured to movefrom a low profile configuration for delivery through the vasculature toa deployed configuration in which the balloon presses against the wallof the renal artery. In yet another embodiment, the neuromodulationassembly 21 can include an expandable mesh configured to move from a lowprofile configuration for delivery through the vasculature to a deployedconfiguration in which the mesh presses against the wall of the renalartery. In any of the foregoing embodiments, the neuromodulationassembly 21 may comprise a fluid dispersion device and/or a vibratorydevice. For example, in certain embodiments, the neuromodulationassembly 21 can disperse a radiopaque substance into the renal artery.

Upon delivery to a target treatment site within a renal blood vessel,the neuromodulation assembly 21 can be further configured to be deployedinto a treatment state or arrangement for delivering energy at thetreatment site and providing therapeutically-effectivemechanically-induced and/or electro-magnetically-induced renalneuromodulation. In some embodiments, the neuromodulation assembly 21may be placed or transformed into the deployed state or arrangement viaremote actuation, e.g., via an actuator 36, such as a knob, pin, orlever carried by the handle 34. In other embodiments, however, theneuromodulation assembly 21 may be transformed between the delivery anddeployed states using other suitable mechanisms or techniques.

The proximal end of the neuromodulation assembly 21 can be carried by oraffixed to the distal portion 20 of the elongated shaft 16. A distal endof the neuromodulation assembly 21 may terminate with, for example, anatraumatic rounded tip or cap. Alternatively, the distal end of theneuromodulation assembly 21 may be configured to engage another elementof the system 10 or treatment device 12. For example, the distal end ofthe neuromodulation assembly 21 may define a passageway for engaging aguide wire (not shown) for delivery of the treatment device usingover-the-wire (“OTW”) or rapid exchange (“RX”) techniques. The treatmentdevice 12 can also be a steerable or non-steerable catheter device(e.g., a guide catheter) configured for use without a guide wire. Bodylumens (e.g., ducts or internal chambers) can be treated, for example,by non-percutaneously passing the shaft 16 and neuromodulation assembly21 through externally accessible passages of the body or other suitablemethods.

The console 26 can be configured to generate a selected form andmagnitude of mechanical energy for delivery to the target treatment sitevia the neuromodulation assembly 21. A control mechanism, such as a footpedal 32, may be connected (e.g., pneumatically connected orelectrically connected) to the console 26 to allow an operator toinitiate, terminate and, optionally, adjust various operationalcharacteristics of the console 26, including, but not limited to,vibration, inflation, and/or power delivery. The system 10 may alsoinclude a remote control device (not shown) that can be positioned in asterile field and operably coupled to the neuromodulation assembly 21.The remote control device can be configured to allow for selectiveactivation of the neuromodulation assembly 21. In other embodiments, theremote control device may be built into the handle assembly 34. Theenergy source 26 can be configured to deliver the treatment energy viaan automated control algorithm 30 and/or under the control of theclinician. In addition, the energy source 26 may include one or moreevaluation or feedback algorithms 31 to provide feedback to theclinician before, during, and/or after therapy.

The energy source 26 can further include a device or monitor that mayinclude processing circuitry, such as a microprocessor, and a display33. The processing circuitry may be configured to execute storedinstructions relating to the control algorithm 30. The energy source 26may be configured to communicate with the treatment device 12 (e.g., viaa cable 28) to control the neuromodulation assembly and/or to sendsignals to or receive signals from the nerve monitoring device. Thedisplay 33 may be configured to provide indications of power levels orsensor data, such as audio, visual or other indications, or may beconfigured to communicate information to another device. For example,the console 26 may also be configured to be operably coupled to acatheter lab screen or system for displaying treatment information, suchas nerve activity before and/or after treatment.

V. Selected Examples of Treatment Procedures for Renal Neuromodulation

FIG. 2 illustrates modulating renal nerves with an embodiment of thesystem 10 (FIG. 1). The treatment device 12 provides access to the renalplexus RP through an intravascular path P, such as a percutaneous accesssite in the femoral (illustrated), brachial, radial, or axillary arteryto a targeted treatment site within a respective renal artery RA. Asillustrated, a section of the proximal portion 18 of the shaft 16 isexposed externally of the patient. By manipulating the proximal portion18 of the shaft 16 from outside the intravascular path P, the clinicianmay advance the shaft 16 through the sometimes tortuous intravascularpath P and remotely manipulate the distal portion 20 of the shaft 16.Image guidance, e.g., computed tomography (CT), fluoroscopy,intravascular ultrasound (IVUS), optical coherence tomography (OCT), oranother suitable guidance modality, or combinations thereof, may be usedto aid the clinician's manipulation. Further, in some embodiments, imageguidance components (e.g., IVUS, OCT) may be incorporated into thetreatment device 12. In some embodiments, the shaft 16 and theneuromodulation assembly 21 can be 3, 4, 5, 6, or 7 French or anothersuitable size. Furthermore, the shaft 16 and the neuromodulationassembly 21 can be partially or fully radiopaque and/or can includeradiopaque markers corresponding to measurements, e.g., every 5 cm.

After the neuromodulation assembly 21 is adequately positioned in therenal artery RA, it can be radially expanded or otherwise deployed usingthe handle 34 or other suitable control mechanism until theneuromodulation assembly is positioned at its target site and in stablecontact with the inner wall of the renal artery RA. The application ofmechanical energy and/or electro-magnetic energy from theneuromodulation assembly can then be applied to tissue to induce one ormore desired neuromodulating effects on localized regions of the renalartery RA and adjacent regions of the renal plexus RP, which layintimately within, adjacent to, or in close proximity to the adventitiaof the renal artery RA. In some embodiments, the application ofmechanical energy and/or electro-magnetic energy to a particulartreatment location can occur for about or less than 1 hour, about orless than 30 minutes, about or less than 20 minutes, or about or lessthan 10 minutes. In a particular example, the neuromodulation assembly21 can contact and impart pressure against the interior wall of therenal artery RA for about or less than 30 minutes. The neuromodulatingeffects may include denervation, alteration or damage to target tissueadjacent to the renal artery. The application of mechanical energy mayachieve neuromodulation along all or at least a portion of the renalplexus RP.

A treatment procedure can include treatment at any suitable number oftreatment locations, e.g., a single treatment location, two treatmentlocations, or more than two treatment locations. In some embodiments,the number of treatment locations receiving treatment (e.g., mechanicalenergy and/or electro-magnetic energy) in a renal artery can be 4-6treatment locations, >6 treatment locations, no less than 8 treatmentlocations, equal to or greater than 8 treatment locations, etc. Thetreatment procedure can also include treatment at a plurality oftreatment locations arranged in a treatment pattern. In one embodiment,the pattern can include a series of treatment locations, e.g.,overlapping and/or non-overlapping. In some embodiments, the treatmentlocations can extend around generally the entire circumference of thevessel, but can still be non-circumferential at longitudinal segments orzones along a lengthwise portion of the vessel. FIGS. 3A-3B, forexample, illustrate a pattern of treatment locations that can be formedon the interior vessel wall along the lengthwise portion of the vesselin accordance with an embodiment of the present technology. For example,and in certain embodiments, the treatment locations 301 (individuallyidentified as 301A-D) can be spaced apart from each other (e.g., by notless than approximately 5 mm) along a longitudinal axis LA of the vessel302 (FIG. 3A). In some embodiments, the treatment locations 301 can bearranged in a pattern around the wall 304 of the blood vessel 302 (suchas a helical/spiral pattern—FIG. 3B). In certain embodiments, and asshown in FIG. 3B, a helical pattern can include at least one treatmentlocation 301 in each of an inferior (301A), anterior (301B), superior(301C) and posterior (301D) position around the wall 304.

In some embodiments, different treatment locations can correspond todifferent portions of the renal artery RA, RA branches, the renal vein,and/or other suitable structures proximate tissue having relatively highconcentrations of renal nerves. The shaft 16 can be steerable (e.g., viaone or more pull wires, a steerable guide or sheath catheter, etc.) andcan be configured to move the neuromodulation assembly 21 betweentreatment locations. At each treatment location, the neuromodulationassembly 21 can be activated to cause modulation of nerves proximate thetreatment location. Activating the neuromodulation assembly 21 caninclude applying various types of mechanical energy and at varyingintensities and for various durations for achieving modulation of nervesproximate the treatment location. In some embodiments, power levels(e.g., force levels, pressure levels, inflation parameters, etc.),intensities and/or treatment duration can be determined and employedusing various algorithms for ensuring modulation of nerves at selectdistances (e.g., depths) away from the treatment location. Furthermore,as noted previously, in some embodiments, the neuromodulation assembly21 can be configured to introduce (e.g., inject) a chemical (e.g., adrug, contrast or other agent) into vessels or target tissue at thetreatment location. Such chemicals or agents can be applied at variousconcentrations depending on treatment location and the relative depth ofthe target nerves.

As discussed, the neuromodulation assembly 21 can be positioned at atreatment location within the renal artery RA, for example, via acatheterization path including a femoral artery and the aorta, oranother suitable catheterization path, e.g., a radial or brachialcatheterization path. Catheterization can be guided, for example, usingimaging, e.g., magnetic resonance, computed tomography, fluoroscopy,ultrasound, intravascular ultrasound, optical coherence tomography, oranother suitable imaging modality. The neuromodulation assembly 21 canbe configured to accommodate the anatomy of the renal artery RA, therenal vein, and/or another suitable structure. For example, theneuromodulation assembly 21 can include a balloon (not shown) configuredto inflate to a size larger than or generally corresponding to theinternal size of the renal artery RA, the renal vein, and/or anothersuitable structure. In some embodiments, the neuromodulation assembly 21can be an implantable device and a treatment procedure can includelocating the neuromodulation assembly 21 at the treatment location usingthe shaft 16 fixing the neuromodulation assembly 21 at the treatmentlocation, separating the neuromodulation assembly 21 from the shaft 16,and withdrawing the shaft 16. Other treatment procedures for modulationof renal nerves in accordance with embodiments of the present technologyare also possible.

CONCLUSION

The above detailed descriptions of embodiments of the technology are notintended to be exhaustive or to limit the technology to the precise formdisclosed above. Although specific embodiments of, and examples for, thetechnology are described above for illustrative purposes, variousequivalent modifications are possible within the scope of thetechnology, as those skilled in the relevant art will recognize. Forexample, while steps are presented in a given order, alternativeembodiments may perform steps in a different order. The variousembodiments described herein may also be combined to provide furtherembodiments. All references cited herein are incorporated by referenceas if fully set forth herein.

From the foregoing, it will be appreciated that specific embodiments ofthe technology have been described herein for purposes of illustration,but well-known structures and functions have not been shown or describedin detail to avoid unnecessarily obscuring the description of theembodiments of the technology. Where the context permits, singular orplural terms may also include the plural or singular term, respectively.

Moreover, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the term “comprising” is used throughout to mean including at least therecited feature(s) such that any greater number of the same featureand/or additional types of other features are not precluded. Further,while advantages associated with certain embodiments of the technologyhave been described in the context of those embodiments, otherembodiments may also exhibit such advantages, and not all embodimentsneed necessarily exhibit such advantages to fall within the scope of thetechnology. Accordingly, the disclosure and associated technology canencompass other embodiments not expressly shown or described herein.

We claim:
 1. A method of treating hypertension in a human patient havinga systolic blood pressure at or above 140 mm Hg, the method comprising:inserting a mechanical device through vasculature of the human patientto a renal blood vessel; pressing a distal portion of the mechanicaldevice against an interior wall of the renal blood vessel, whereby thedistal portion imparts mechanical force against the interior wall in amanner that at least partially disrupts function of renal neural fiberswithout delivery of electrical energy to the renal neural fibers,wherein disrupting function of the renal neural fibers results in atherapeutically beneficial decrease in blood pressure of the patient;and removing the mechanical device from the renal blood vessel afterpressing the device against the interior wall.
 2. The method of claim 1wherein removing the mechanical device from the renal blood vesselincludes removing the distal portion of the mechanical device from thepatient.
 3. The method of claim 1 wherein the mechanical devicecomprises a basket having a plurality of expandable legs, and whereinpressing a distal portion of the mechanical device against an interiorwall of the renal blood vessel comprises transforming the basket betweena low profile configuration for delivery through the vasculature to adeployed configuration in which the legs press against the wall of therenal blood vessel.
 4. The method of claim 1 wherein the mechanicaldevice comprises a balloon, and wherein pressing a distal portion of themechanical device against an interior wall of the renal blood vesselcomprises transforming the balloon from a low profile configuration fordelivery through the vasculature to a deployed configuration in whichthe balloon presses against the wall of the renal blood vessel.
 5. Themethod of claim 1 wherein the mechanical device comprises an expandablemesh, and wherein pressing a distal portion of the mechanical deviceagainst an interior wall of the renal blood vessel comprisestransforming the mesh from a low profile configuration for deliverythrough the vasculature to a deployed configuration in which the meshpresses against the wall of the renal blood vessel.
 6. The method ofclaim 1 wherein the mechanical device comprises a probe having abendable distal tip, and wherein pressing a distal portion of themechanical device against an interior wall of the renal blood vesselcomprises pressing the distal tip of the probe against the wall of therenal blood vessel.
 7. The method of claim 1 wherein pressing a distalportion of the mechanical device against an interior wall of the renalblood vessel comprises imparting force against the interior wall at aplurality of treatment locations, and wherein the treatment locationsare spaced apart from each other and arranged in a helical pattern aboutan interior wall of the renal blood vessel, and further wherein thehelical pattern includes at least one treatment location in each of aninferior, anterior, superior and posterior position about the interiorwall.
 8. The method of claim 1 wherein pressing a distal portion of themechanical device against an interior wall of the renal blood vesselcomprises imparting force against the interior wall for about 30 minutesor less.
 9. The method of claim 1 wherein the therapeutically beneficialdecrease in blood pressure of the patient is a decrease in bloodpressure of at least about 12 mm Hg.
 10. The method of claim 1 whereinthe therapeutically beneficial decrease in blood pressure of the patientis a decrease in office blood pressure of at least about 14 mm Hg. 11.The method of claim 1 wherein the therapeutically beneficial decrease inblood pressure of the patient is a decrease in office blood pressure ofat least about 21 mm Hg.
 12. The method of claim 1 wherein thetherapeutically beneficial decrease in blood pressure of the patient isa decrease in ambulatory blood pressure of at least about 5 mm Hg. 13.The method of claim 1 wherein, prior to inserting the mechanical device,the patient is on a maximum tolerable dosage of one or moreantihypertensive medications.
 14. The method of claim 1 wherein thepatient achieves the therapeutically beneficial decrease in bloodpressure no more than 6 months after disrupting function of the renalneural fibers.
 15. The method of claim 1 wherein imparting mechanicalforce against the interior wall via the mechanical device in a mannerthat at least partially disrupts function of renal neural fibers furthercomprises imparting mechanical force without delivery of drug therapy tothe renal neural fibers.
 16. The method of claim 1 wherein impartingmechanical force against the interior wall via the mechanical device ina manner that at least partially disrupts function of renal neuralfibers further comprises imparting mechanical force without delivery ofcryotherapy to the renal neural fibers.